Research Focus

We have recently established a protocol for transcription factor (TF) programming of human fibroblasts into hepatocyte-like cells. Principal component analysis of the transcriptome shows a shift in global gene expression towards primary hepatocytes. The cells secrete albumin, express various Cytochrom P450 activities and express many liver specific metabolic enzymes. In our current program we aim to further refine the protocol by testing over-expression of other TF candidates and also miRNA´s and to demonstrate fully functional xenobiotic activity for in vitro testing of drugs and toxins. The program has also been extended to direct reprogramming of profibrogenic myofibroblasts into hepatocytes in vivo for therapeutic remodeling of chronic liver diseases.

Therapeutic transplantation of hepatocyte like cells derived from ES or iPS cells in to the liver remains difficult, since these cells engraft poorly in the target organ. We have developed novel transplantation techniques including targeted ablation of resident hepatocytes to induce expansion of gene corrected transplanted cells. Proof of principle has already been demonstrated with primary mouse hepatocytes. In our future work we will also examine, whether iPSC or ES derived hepatocytes can integrate into and repopulate Fah(-/-) mouse livers using the cell sheet technologies. We have recently generated AAV8 vectors for targeted CRISP/R-Cas9 mediated correction of the FAH gene in Fah(-/-) with high degrees of homology directed repair. Future studies will focus on increasing the efficacy of gene repair in the liver in vivo and on novel application technologies, which would be suitable for clinical application. We finally develop RNA based therapies for a variety of liver diseases based on RNA replicon technologies and non-viral delivery methods for RNA molecules.